Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences

2010, 5 (1): 1-12

Improvement of solubility and dissolution properties of
ketoconazole by solid dispersions and inclusion complexes
Gehan Balata*, Mahmoud Mahdi, Rania Abu Bakera
Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
Received 19 June 2009; Revised 26 November 2009; Accepted 24 December 2009
__________________________________________________________________________________
___________________________
Abstract
Purpose: The aim of this study was to prepare inclusion complexes and solid dispersions of
ketoconazole to improve its dissolution
rate and hence its antifungal properties for the effective therapy of candidaiasis. Methods: The
solvent evaporation method was used
to prepare ketoconazole inclusion complexes in -cyclodextrin with different molar ratios of drug to
carrier (1: 1, 1: 2.5 and 1: 5). In
addition, solid dispersions of ketoconazole in polyvinylpyrrolidone k-17 with different weight ratios
of drug to carrier (1: 1, 1: 5 and
1: 10) were prepared. Moreover, the effect of the molecular weight of polyvinylpyrrolidone was also
investigated. A phase solubility
method was used to evaluate the effect of the tested carriers on the aqueous solubility of
ketoconazole. The dissolution of all the
preparations was tested using the USP paddle method. The interaction of ketoconazole with the
carriers was evaluated by differential
scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The selected ketoconazole inclusion
complex or ketoconazole solid
dispersion was incorporated in different topical bases by trituration and compared with the pure
drug and the commercial ketoconazole
cream for in-vitro drug release and antifungal activity. Results: According to the results of this
investigation, the solubility and
dissolution rates of ketoconazole were significantly increased by solid dispersions and cyclodextrin
complexes as well as their physical
mixtures. However, the dissolution enhancement of ketoconazole was dependent on the carriers
used and the nature of presentation
of ketoconazole in the carriers (physical mixture/solid dispersion/molecular inclusion). The
ketoconazole-beta cyclodextrin inclusion
complex at 1: 5 molar ratio showed the highest dissolution of all the preparations (DE% = 71.1
1.9). The results from DSC and XRPD
indicated the presence of ketoconazole in an amorphous form in both the inclusion complex and
solid dispersion, accounting for the
occurrence of a strong interaction between ketoconazole and beta cyclodextrin/or
polyvinylpyrrolidone in the solid state. Improved
drug release was found with topical formulations containing ketoconazole in the form of a solid
dispersion or inclusion complex.
However, hydroxypropylmethyl cellulose gel base showed maximum drug release compared with
the other topical bases. The antifungal
data agreed with the in vitro results and proved the superiority of the prepared vaginal gel
(ketoconazole/-cyclodextrin complex in
hydroxypropylmethyl cellulose gel) to the commercial ketoconazole cream. Conclusion: An
increased solubility and dissolution rate of
ketoconazole can be achieved by complexation with beta cyclodextrin and solid dispersion formation
with polyvinylpyrrolidone k-17.
Keywords: Ketoconazole; -cyclodextrin; Polyvinylpyrrolidone; Topical activity; Antifungal activity
__________________________________________________________________________________
___________________________
1. Introduction
It has been estimated that 75% of all women
experience vaginal candidiasis once in their life
time, with up to 5% suffering from recurrent vaginal
candidiasis [1]. From such a perspective, topical
treatment of Candida vaginitis could be a rational choice
for management of localized infection. For effective
therapy, intravaginally delivered drugs should achieve
high concentration at the site of infection. Therefore,
an increase in the solubility and rapid release of ketoconazole
is essential for such preparations. It has been
reported that poor water solubility and "wettability"
of the drug can cause problems with drug release and
bioavailability in various pharmaceutical forms [2].
There have been numerous efforts to improve the
dissolution rate of drugs. These include, reducing the
particle size, formation of inclusion complexes with
cyclodextrins, solubilization in surfactant systems, using
pro-drugs and drug derivatization and formation of solid
dispersions [3]. The formulation of solid dispersions
__________
*Corresponding author. Address: Department of Pharmaceutics,
Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Tel: +20-55-2303266; Fax: +20-55-2303266
E-mail: mmdh_zaghloul@yahoo.com
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
is one of the most popular ones [4-7], although few
marketed products rely on this concept. Historically,
water-soluble carriers such as high molecular weight
polyvinylpyrrolidones (PVP) have been the most
common carriers used for solid dispersions (SDs). For
solid dispersions, PVP k-12 to k-30 (Mw 250050,000)
have been widely used [8]. Mechanisms suggested to
be responsible for the improved aqueous solubility/
dissolution properties of solid dispersions include
reduction of the particle size of the incorporated drug,
partial transformation of the crystalline drug to the amorphous
state, formation of solid solutions, formation of
complexes, reduction of aggregation and agglomeration,
improved wetting of the drug and solubilization of the
drug by the carrier at the diffusion layer [9-11]. It is
generally accepted, that often more than one of these
phenomena determine the rate and extent of dissolution.
It has been shown that the methods for the preparation
of solid dispersions are simple and less expensive than
other techniques [12-16].
Cyclodextrins (CDs) are a family of cyclic oligosaccharides
which can form inclusion complexes with
large organic molecules thus improving their dissolution
rate. The most common are the -, -, and -cyclodextrins
[17].
In the literature, some information is available on
the enhancement of drug release from different topical
bases using solid dispersion and inclusion complex
techniques [18-20].
Ketoconazole (KET), an azole antifungal agent,
is used to relieve the external symptoms (candidal
vulvitis) of vaginal thrush (candidal vaginitis) but it has
a poor aqueous solubility making it difficult to dissolve
in water [21].
Previous studies have been carried out on KET and
-cyclodextrin or its derivatives in solution and the
solid phase [22-25]. Continuing that research, here we
report the effect of polyvinyl pyrrolidone polymers on
ketoconazole solubility compared with -cyclodextrin.
Moreover, the influence of a solid dispersion and an
inclusion complex preparation on the in vitro drug
release from different topical bases and its antifungal
activity was investigated.
2. Materials and methods
2.1. Materials
Ketoconazole (KET), polyvinyl pyrrolidone k-17 (PVP
k-17), (PVP k-25) and (PVP k-30) were obtained as
gifts from Memphis Co. (Cairo, Egypt). - Cyclodextrin (-
CD) (Mw 1135), hydroxypropylmethyl cellulose (50 cp)
and sabouraud's dextrose agar were purchased from
Sigma-Aldrich (St Louis, MO, USA). Methanol, ethanol,
white petrolatum, liquid paraffin, bees wax, olive oil,
borax, stearic acid, cirtic acid, sodium hydroxide, hydrochloric
acid and sodium lauryl sulphate were purchased
from El-Gomhoria Co. (Cairo, Egypt). A semipermeable
cellophane membrane 30/32 was supplied by (Fischer
Scientific Co., London, England).
2.2. Phase solubility studies
Solubility studies were performed according to the
method described by Higuchi and Connors [26]. An
excess of drug (10 mg) was added to 10 ml water or
aqueous carrier solutions of different concentrations
(01.8% for -CD or 1%20% for PVP polymers)
in 25-ml stopper conical flasks and shaken at 25C in a
thermostatically controlled water bath (Julabo SW 20C,
Osaka, Japan). At equilibrium after 4 d (for -CD) or
2 d (for PVP polymers), aliquots were withdrawn, filtered
(0.22 m pore size, Whatman UK), suitably diluted with
methanol and the drug content spectrophotometrically
assayed at 260 nm (Shimadzu UV-160A Spectrophotometer,
Shimadzu, Japan). Each experiment was carried
out in triplicate.
The apparent 1: 1 stability constant was calculated
from the solubility data using the following formula:
Where S0 is the intrinsic solubility of ketoconazole.
2.3. Preparation of solid inclusion complexes
Solid inclusion complexes of KET and -CD were
prepared by the co-evaporation method in the following
Slope
S0 (1Slope)
K ____________ 1:1 =
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
molar ratios, 1: 1, 1: 2.5 and 1: 5 [27]. KET and -CD
were dissolved at 40C in the lowest volume of 50%
ethanol (which is necessary to obtain solution) and
stirred for 30 min. Then, the solvent was evaporated
in a vacuum oven at 50C until complete drying was
obtained as shown by constant weight.
2.4. Preparation of solid dispersions
KET in SDs with PVP K-17 in different weight ratios
(1: 1, 1: 5, 1: 10, w/w) were separately obtained by
the conventional solvent evaporation method [28]. KET
and PVP K-17 were dissolved in a minimum volume of
methanol and the solvent was removed under vacuum
in a rotavapor at 65C and 80 r/min. The resultant solid
dispersion was pulverized using a mortar and pestle,
passed through a 250-m sieve (mesh size 60), kept in
vacuum-desiccator at 40C for 24 h, and then stored in
a desiccator at room temperature.
To study the effect of the PVP molecular weight,
SDs with PVP k-25 and PVP k-30 were prepared as
described above at the weight ratio that produced the
best dissolution results.
2.5. Preparation of physical mixtures
Physical mixtures of KET (< 250 m) were prepared
by mixing the appropriate amounts of KET and -CD
or PVP k-17 in geometric proportions using a mortar
and pestle, until a homogeneous mixture was obtained.
The physical mixtures were subsequently stored at
room temperature in screw capped glass vials until use.
2.6. Evaluation of drug content
About 20 mg of each of the prepared products
(cyclodextrin complexes, solid dispersions or their
physical mixtures) was placed in a 25-ml volumetric
flask. Methanol (10 ml) was added, mixed thoroughly
and sonicated for 30 min. The volume was made up
to the mark with methanol and then passed through
Whatman filter paper No. 41. The solution was suitably
diluted with the same solvent and the drug content
spectrophotometrically assayed at 260 nm [29].
The percentage drug content was calculated for all
batches using the equation:
Where KETact is the actual KET content in 20 mg
product and KETtheor is the theoretical amount of KET
in 20 mg product.
2.7. Dissolution studies
Dissolution studies were performed in triplicate with
a Pharma Test dissolution tester (Pharma Test SP6-400,
Hamburg, Germany) in distilled water (500 ml) at
37 0.2C, using a paddle rotating at 100 r/min. The
drug and solid products, each containing 20 mg drug,
were subjected to dissolution testing. At fixed time,
samples (5 ml) were withdrawn and filtered (Whatman
filter paper No. 41), diluted with methanol and the drug
content was spectrophotometrically assayed at 260 nm.
The initial volume was maintained by adding 5 ml of
fresh dissolution medium. The dissolution efficiency
(DE) was calculated from the area under the dissolution
curve at time t (measured using the trapezoidal rule) and
expressed as a percentage of the area of the rectangle
described by 100% dissolution over the same time [30].
2.8. Differential scanning calorimetry (DSC)
DSC analysis was performed using a Model DT-60
DSC (Shimadzu). Samples weighing 1.5 mg were
heated in hermetically sealed aluminum pans over a
temperature range of 30C200C at a constant rate of
10C/min under a nitrogen steam.
2.9. X-ray powder diffractometry (XRPD)
X-ray powder diffraction patterns were recorded on
a Siemens Kristallofex D-5000 powder diffractometer
with CuK radiation. The scanning rate employed was
8/min over a 2 range of 080.
Drug content% =
KETact
KETtheor
________ 100
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
2.10. Preparation of topical vehicles
All topical bases were formulated to contain 2% KET
or its equivalent in a 1: 5 molar ratio (-CD complex)
or 1: 1 weight ratio (PVP k-17 solid dispersion). Table 1
shows the formulae of the different topical bases
prepared. Base 1 was prepared by levigating the drug
alone or its solid product with liquid paraffin then the
melted petrolatum was added and the mixture was stirred
until it congealed. Bases 2,3 were prepared by melting
the oily phase in a water bath at 70C, then the aqueous
phase (previously heated to 70C) was added and the
mixture was removed from water bath and stirred until
it congealed. Finally, KET or its solid products were
added by trituration. Also, 2% (w/w) hydroxypropylmethylcellulose
(HPMC) gel base was prepared by
dispersing the required amount of HPMC in Srensen's
citrate buffer pH 4.5. The dispersion was mixed using
a magnetic stirrer until a clear transparent gel free of
air bubbles was obtained. The resultant gel mass was
left overnight to allow complete swelling, then KET
or its solid products were added by trituration. HPMC
was specially selected as a gel base due to its excellent
mucoadhesive properties [31, 32].
2.11. In-vitro drug release
A 2.5 g sample of each formulation was accurately
weighed and placed on a semipermeable cellophane
membrane (previously immersed in distilled water for
20 h) to occupy a circle 2.9 cm in diameter. The loaded
membrane was stretched over the lower open end of
a glass tube 2.9 cm in diameter and made water tight
using a rubber band. The tube was then immersed in
a beaker containing 150 ml Srensen's citrate buffer,
pH 4.5. Sodium lauryl sulphate 1% (w/w) was added
to the medium to ensure sink conditions. The system
was maintained for 6 h at 37C in a thermostatic
shaking water bath at 100 r/min. Samples (2 ml) were
withdrawn at intervals of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 5
and 6 h, the volume of each sample was replaced by the
same volume of fresh medium to maintain a constant
volume, and the KET content of the samples was
determined spectrophotometrically at max = 260 nm.
2.12. Microbiological studies
The anti-candidal activity of the drug in an HPMC gel
base (chosen as the best) containing KET alone, IC with
-CD (1: 5, molar ratio) or SD with PVP k-17 (1: 1, w/w)
compared with commerecial ketoconazole cream was
determined using Candida albicans [35]. The suspension
of Candida albicans was streaked evenly on triple plates
of Sabouraud dextrose agar. Agar cups were cut from the
seeded agar medium using a sterile cork borer. These
cups were filled with 100 mg of different formula prepared
with 2% drug and also without drug. Moreover,
100 mg of commercial ketoconazole cream (2% KET)
was used for comparison. Plates were then incubated at
37C for about 3 d and the diameters of the inhibition
zones were measured and the inhibition dis-tance calculated.
The bases without KET were used as controls.
1-Oleaginous base [33] Liquid paraffin 5% , white petrolatum 95%
2-Emulsion base (W/O)* Bees wax 12%, olive oil 12.5%, white petrolatum 56%, borax 0.5%, water
19%
3-Hydrophilic ointment (O/W) [33] Sodium lauryl sulphate 1%, propylene glycol 12%, stearyl alcohol
25%,
white petrolatum 25%, water 37%
4-Gel base [32] 2% Hydroxypropyl methylcellulose (HPMC), 98% water
5-Commercial ketoconazole cream 2% [34]
An aqueous cream vehicle consisting of propylene glycol, purified water,
cetyl alcohol, stearyl alcohol, isopropyl myristate, sorbitan monostearate,
polysorbate 60, polysorbate 80, and sodium sulfite, anhydrous
Table 1
Components of different topical bases.
*The water-in-oil vehicle was an extemporaneous preparation.
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
3. Results and discussion
3.1. Influence of cyclodextrin on the solubility of
ketoconazole
The solubility of ketoconazole in water at 25C was
found to be 13.3 g/ml (0.025 mM), which is in good
agreement with the reported value by Connors and Elder [36],
who found that the aqueous solubility of KET at 25C is
17 g/ml. The solubility of KET was markedly affected
by the presence of -CD. The solubility of KET in 1.6%
-CD aqueous solution was 1627.9 g/ml (3.06 mM)
representing a 122-fold increase in solubility compared
with pure drug. The obtained phase solubility diagram
was linear with positive deviation from linearity at higher
-CD concentrations (Fig. 1) and could be classified
as AM type according to Higuchi and Connors [26].
The stability constant value obtained for the KET-CD
complex was 268.9 M-1, which indicated that the KET-
-cyclodextrin complex at a 1: 1 molar ratio is suitably,
stable [26].
3.2. Influence of PVP molecular weight on the solubility
of ketoconazole
The effect of the PVP molecular weight on the
solubility of KET is shown in Fig. 2 and the data were
evaluated statistically by one-way analysis of variance
(ANOVA).The increase in solubility was linear with
respect to the carrier concentration suggesting the
features of an AL type solubility phase diagram [26].
Although a statistically insignificant difference (P > 0.05)
was obtained, PVP k-17 had a higher solubility than the
other PVPs. Collett and Kesteven [37] have reported
that the lower the molecular weight of PVP, the greater
is the increase in solubility of allopurinol. At 20% PVP
k-17 the increase in solubility at 25C was 172.5-fold
compared with that of the pure drug. The increase in
solubility in the presence of different forms of PVP can
probably be explained by the increased wettability of
KET. Indeed, PVP polymers cause a reduction in the
interfacial tension between the drug and the dissolving
solution [38]. Moreover, it was suggested that PVP polymers
might form soluble complexes with KET [13, 39].
The stability constant of KET with PVP k-17, PVP
k-25 and PVP k-30 was found to be 141, 179 and 191 M-1,
respectively, indicating that the ketoconazole and the
carrier dispersions are sufficiently stable. In fact, the
values of the obtained stability constants were always
within the range 1001000 M-1, which is believed to be
ideal. Actually, smaller values of the stability constant
indicate too weak an interaction between drug and carrier,
while higher values are symptomatic of an incomplete
drug release from the complex [40]. So the values we
obtained are considered ideal and are expected to be
stable.
0
400
800
1200
1600
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Concentration of -CD (%)
Solubility (g/ml) Solubility (g/ml)
0
500
1000
1500
2000
2500
3000
0 2 4 6 8 10 12 14 16 18 20
Concentration of PVP (%)
PVP k-17
PVP k-25
PVP k-30
Fig. 2. Phase solubility diagram of KET in the presence of PVP
of different molecular weights in distilled water at 25C.
Fig. 1. Phase solubility diagram of KET in the presence of -CD
in distilled water at 25C.
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
3.3. Evaluation of drug content
The percentage KET in the samples ranged from
98.2 0.2 to 100.2 0.1 (n = 3). This indicated that KET
was uniformly distributed in all the samples.
3.4. Dissolution studies
The in vitro dissolution profiles of the drug, PMs and
inclusion complexes or SDs are shown in Fig. 3Fig. 5.
The extent of dissolution after 30 and 120 min and the
dissolution efficiency after 120 min are presented in
Table 2 and Table 3.
It was evident that the dissolution rate of pure KET
was slow, less than 16% of the drug being dissolved
within 120 min. This is could be ascribed to poor
wettability and /or agglomeration or particle size [41].
Compared with that of pure KET, the dissolution rate of
KET from its physical mixtures appeared faster.
3.4.1. Influence of cyclodextrin complex formation on
the dissolution properties of KET
In fact, the dissolution results from complexes
with different drug: -CD molar ratios did not
follow a specific pattern (Fig. 3). However, the
inclusion complex at a molar ratio of 1: 5 showed the
greatest dissolution improvement. About 95.5% of
drug was released after 2 h from the 1: 5 inclusion
complex (DE% = 71.1 1.9) compared with 75.2%
(DE% = 12.1) and 15.2% (DE% = 5.6 1.7) from the
1: 5 physical mixture and KET alone, respectively.
This enhancement can be attributed to the formation of
an inclusion complex of the drug with -CD and/or the
conversion of the drug to an amorphous state or nearly
amorphous state [42]. It is clear that drug dissolution
from the complexes was faster than that from the
physical mixtures. About 17.1%, 8.2% and 66.3% of
drug dissolved after 30 min from 1: 1, 1: 2.5 and 1: 5
complexes, respectively, compared with 0% of drug
dissolved from the corresponding physical mixtures.
The Improved KET solubility obtained with physical
mixtures compared with KET alone (Table 2) can be
attributed to the local solubilization action of CD,
0
20
40
60
80
100
120
0 15 30 45 60 75 90 105 120
Time (min)
KET released (%)
KET 1: 1 PM
1: 2.5 PM 1: 5 PM
1: 1 IC 1: 2.5 IC
1: 5 IC
0
20
40
60
80
100
120
0 15 30 45 60 75 90 105 120
Time (min)
KET released (%)
KET 1: 1 PM
1: 5 PM 1: 10 PM
1: 1 SD 1: 5 SD
1: 10 SD
0
20
40
60
80
100
120
0 15 30 45 60 75 90 105 120
Time (min)
KET released (%)
KET PVP k-17
PVP k-25 PVP k-30
Fig. 4. Dissolution profiles of KET from its different systems
with PVP k-17 in distilled water at 37C.
Fig. 5. Effect of PVP molecular weight on the dissolution
behavior of KET.
Fig. 3. Dissolution profiles of KET from its different systems
with -CD in distilled water at 37C.
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
operating in the microenvironment on the hydrodynamic
layer surrounding the drug particles, which improves
KET wettability and/or solubility. Also, the in situ
formation of a readily soluble complex in the
dissolution medium additionally contributed to the drug
release from the prepared physical mixtures [19].
3.4.2. Influence of solid dispersion formation on the
dissolution properties of KET
It is clear from Fig. 4 that solid dispersions of KET
with PVP k-17 showed improved dissolution when
compared with physical mixtures and pure drug. The
dissolution profile of the solid dispersion (1: 1 weight
ratio) showed that 100% of the drug was released in
120 min (DE% = 50.8 3.4) while the corresponding
values for the 1: 1 physical mixture and pure drug
were 27.3% and 15.2%, respectively. Formulation of
a solid dispersion further improves the dissolution in
comparison with the physical mixture by reducing
the drug particle size, formation of drug-carrier solid
solutions, and transformation of the drug into a faster
dissolving amorphous state and by a more intimate
contact between the carrier and the drug [29].
In studying the effect of the PVP molecular weight
on the dissolution properties of KET, it was observed
that better results were obtained with the lower
molecular weight PVP k-17 than the higher molecular
weight PVP k-25 or PVP k-30 (Table 3). This could be
due to lower stability constant of PVPk-17 dispersion
and subsequent rapid drug release. Moreover, the
mechanism of dissolution of the solid dispersion in
PVP k-30 is predominantly diffusion-controlled due to
the high viscosity of PVP k-30 [43]. These results were
in agreement with those of Narang and Srivastava regarding
the dissolution enhancement of clofazimine [44].
3.5. Differential scanning calorimetry (DSC)
The thermal behavior of ketoconazole solid products
demonstrated the presence of intense solid-state
interactions between KET and -CD/PVP k-17.
DSC curves of the pure drug, -CD, 1: 5 molar
physical mixture and 1:5 molar inclusion complex are
shown in Fig. 6. The DSC curve of the drug showed a
sharp endothermic peak at 149.26C (H = 90.72 J/g)
corresponding to the melting point of KET. The DSC
curve of -CD showed a broad endothermic peak at
90.73C (H = 287.2 J/g), which is related to the
removal of adsorbed water [31]. The DSC curve of the
1: 5 molar ratio physical mixture of the drug and -CD
showed two broad endothermic peaks, one broad peak
System Q30 (%) Q120 (%) DE (%)
KET 3.1 15.2 4.2 5.6 1.7
KET- -CD (PM):
1: 1 0 51.2 9.5 7.4 0.4
1: 2.5 0 77.6 10.4
1: 5 0 75.2 12.1
KET- -CD (IC):
1: 1 17.1 3.8 49.4 10 25.5 6.2
1: 2.5 8.2 34.2 15.6 2.5
1: 5 66.3 1.04 95.5 10.6 71.1 1.9
Table 2
Dissolution parameters ( SEM) of KET from different ketoconazole-
-CD physical mixtures and inclusion complexes in
distilled water.
Q30: Percentage of drug dissolved after 30 min; Q120 : Percentage of
drug dissolved after 120 min and DE: Dissolution efficiency.
System Q30 (%) Q120 (%) DE (%)
KET 3.1 15.2 4.2 5.6 1.7
KET-PVP k-17 (PM):
1: 1 0 27.3 5.2 9.2 0.4
1: 5 10.5 3.6 44.6 3.3 19.3 3.2
1: 10 34 11.5 90.7 7.6 41.7 8.1
KET-PVP k-17 (SD):
1: 1 48.5 5 100 50.8 3.4
1: 5 33.2 10.1 100 13.8 43.9 10
1: 10 31.6 10.1 100 12.3 49 4.7
KET-PVP k-25 (SD) 1: 1 0 43.8 12.4 8.5
KET-PVP k-30 (SD) 1: 1 0 35.9 4.8 7.7 1.6
Table 3
Dissolution parameters ( SEM) of KET from different
ketoconazole-PVP physical mixtures and solid dispersions in
distilled water.
Q3: Percentage of drug dissolved after 30 min; Q120: Percentage of drug
dissolved after 120 min and DE: Dissolution efficiency.
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
at 149.7C (H = 1.81 J/g ) corresponding to KET and
the other broad peak at 99.4C corresponding to -CD
(H = 221.77 J/g). The DSC curve of the 1: 5 molar
ratio inclusion complex of the drug and -CD showed
two broad endothermic peaks, one broad peak at 142.9C
(H = 1.89 J/g) corresponding to KET and the other
broad peak at 91.95C (H = 154.26 J/g) corresponding
to -CD. It is clear that the peak temperature in the
inclusion complex was slightly shifted with respect to
the drug alone. In addition, there was a reduction in
ketoconazole H values in both the inclusion complex
and physical mixture compared with the pure drug.
However, the reduction in the -cyclodextrin H value
in the inclusion complex compared with pure -CD
was greater than that in the physical mixture. From
these results one can conclude that there is complete
complexation in the inclusion complex rather than
partial complexation in the physical mixture.
The DSC curves of the pure drug, PVP k-17, 1: 1
weight ratio physical mixture and 1:1 weight ratio solid
dispersion are shown in Fig. 7. The DSC curve of PVP
k-17 showed a large endotherm over the temperature
range 50 to 100C (H = 164.57 J/g) associated with
water loss [45]. The DSC curve of the 1: 1 weight ratio
physical mixture of the drug and PVP k-17 showed two
broad endothermic peaks, one broad peak at 149.5C
(H = 46.46 J/g ) corresponding to KET and the other
broad peak at 49.79C corresponding to PVP k-17
(H = 104.44 J/g). The DSC curve of the 1: 1 weight
ratio solid dispersion of the drug and PVP k-17 showed
two broad peaks, one endothermic broad peak at 140.3C
(H = 6.11 J/g) corresponding to KET and one exothermic
broad peak at 64.22C (H = 16.36 J/g) corresponding
to PVP k-17. The peak temperatures in the physical
mixture and solid dispersion were slightly shifted with
respect to the drug alone. The reduction in the solid
dispersion H value compared with the pure drug and
physical mixture showed drug amorphization.
3.6. X-ray powder diffractometry (XRPD)
The XRPD patterns of KET, -CD, 1: 5 molar
physical mixture and 1: 5 molar inclusion complex are
shown in Fig. 8. The presence of many different peaks
in the XRPD pattern indicated that the drug was in
crystalline form and the peaks of XRPD at 17.4, 19.3,
19.9 and 23.7 were selected as characteristic peaks
in the mixture. The XRPD pattern of -CD showed
lower crystallinity. The diffraction patterns of the
physical mixture showed superposition of the spectra
of each component with marked reduction in intensity
compared with the pure drug. In contrast, the diffraction
patterns of the inclusion complex were diffuse and the
disappearance of important ketoconazole crystalline
peaks indicated the entirely amorphous nature of the
drug in the complex.
The XRPD patterns of KET, PVP k-17; 1: 1 weight
ratio physical mixture and 1:1 weight ratio solid dispersion
are shown in Fig. 9. The amorphizing power of
PVP toward the drug was clear in the solid dispersion
system, since no crystalline KET was detected. However,
the simple blending with PVP caused a partial decrease
in KET crystallinity, probably as a consequence of a
loosening of crystal forces of KET finely dispersed
within the amorphous PVP [46]. Evidently, some
characteristic peaks, indicative of the presence of
residual KET were detectable in the physical mixture.
3.7. Influence of cyclodextrin complex and solid dispersion
on in-vitro drug release from different topical bases
The in vitro release profiles of KET from different
topical bases containing KET alone, IC with -CD (1: 5,
molar ratio) or SD with PVP k-17 (1: 1, w/w) compared
with its release from commercial ketoconazole cream,
are represented in Fig. 10. It was observed that the in
vitro release of the drug was low from oleaginous and
cream bases, while it was higher from the hydrogel
base (HPMC). In creams, owing to their biphasic
nature, partitioning of the drug occurs in two phases,
resulting in slower release of drug, while in the case of
gel base, the drug diffusion occurs through the aqueous
phase and hence it offers a greater drug diffusion and
release [47]. Moreover, the incorporation of the drug
as IC with -CD further increased the release from the
hydrogel base (40%) compared to only (29%) from the
commercially available cream. This may be ascribed to
enhancing drug solubility by cyclodextrin complexation
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
Endotherm
50 100 150
Temperature (C)
KET
(H = 90.72 J/g)
-CD
(H = 287.2 J/g )
1: 5 PM
(HKET = 1.81 J/g )
(H-CD = 221.77 J/g)
1: 5 IC
(HKET = 1.89 J/g )
(H-CD = 154.26 J/g)
Fig. 6: DSC curves of KET and binary systems with -CD.
Fig. 6. DSC curves of KET and binary systems with -CD.
KET
Endotherm
PVP k-17
1: 1 PM
1: 1 SD
(H = 90.72 J/g)
(H = 164.57 J/g)
(HKET = 46.46 J/g)
(HKET = 6.11 J/g)
(HPVP = 104.44 J/g)
50 100
(HPVP = 16.36 J/g)
150
Temperature (C)
Fig. 7: DSC curves of KET and binary systems with PVP k-17.
Fig. 7. DSC curves of KET and binary systems with PVP k-17.
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
1 0
10 20 30 40
Intensity
KET
-CD
1: 5 PM
1: 5 IC
2 ( )
Fig. 8: X-ray diffraction patterns of KET and binary systems with -CD.
2 ( )
10 20 30 40
KET
PVP k-17
1: 1 PM
1: 1 SD
Intensity
Fig. 9: X-ray diffraction patterns of KET and binary systems with PVP k-17.
Fig. 8. X-ray diffraction patterns of KET and binary systems with
-CD.
Fig. 9. X-ray diffraction patterns of KET and binary systems with
PVP k-17.
0
10
20
30
40
KET released (%)
Cream KET alone 1: 1 PVP 1: 5 -CD
(D)
(A)
0
10
20
30
40
0 1 2 3 4 5 6
Time (h)
KET released (%)
Oleaginous
HPMC gel
O/W cream
W/O cream
(B)
0
10
20
30
40
0 1 2 3 4 5 6
Time (h)
KET released (%)
Oleaginous
HPMC gel
O/W cream
W/O cream
(C)
0
10
20
30
40
0 1 2 3 4 5 6
Time (h)
KET released (%)
Oleaginous
HPMC gel
O/W cream
W/O cream
Fig. 10. Release profiles of KET alone (A) or KET solid products (B) and (C) from different topical bases
across cellophane membrane
in comparison with commercial ketoconazole cream (D) in srensen's citrate buffer pH 4.5 at 37C.
0
10
20
30
40
KET released (%)
Cream KET alone 1: 1 PVP 1: 5 -CD
(D)
(A)
0
10
20
30
40
0 1 2 3 4 5 6
Time (h)
KET released (%)
Oleaginous
HPMC gel
O/W cream
W/O cream
(B)
0
10
20
30
40
0 1 2 3 4 5 6
Time (h)
KET released (%)
Oleaginous
HPMC gel
O/W cream
W/O cream
(C)
0
10
20
30
40
0 1 2 3 4 5 6
Time (h)
KET released (%)
Oleaginous
HPMC gel
O/W cream
W/O cream
Ketoconazole solid dispersions and inclusion complexes/Asian Journal of Pharmaceutical Sciences
2010, 5 (1): 1-12
11
and increasing the overall amount of drug released from
the gel base. Jugi et al., had previously mentioned that
cyclodextrins solubilize lipophilic drugs in the aqueous
vehicle and deliver the drug molecules to the barrier
surface where complex dissociation and drug permeation
across semipermeable membrane occurred [19].
3.8. Influence of cyclodextrin complex and solid dispersion
formation on the anti-candidal activity of KET
The inhibiting capability of KET on the growth of
Candida albicans is shown in Table 4. It was observed
that KET was more readily released from HPMC gel
base containing cyclodextrin complex than from the same
vehicle with PVP solid dispersion or KET alone. Moreover,
KET complexed with cyclodextrin exhibited significant
antifungal activity (larger zone of inhibition indicating
prolonged antifungal activity) compared to the
marketed formulation. The activity ranking agrees with
both the solubility and drug release ranking observed
for these formulations. Similar results were obtained by
Van Doorne et al. [48] and Perdomo-Lpez et al. [49].
4. Conclusion
This study clearly showed that the addition of carriers
especially -CD and PVP k-17 to KET improved its
dissolution rate. Solvent evaporation method proved to
be an efficient and simple method for the preparation
of ketoconazole- cyclodextrin complexes. The present
study also showed that incorporation of the drug as -CD
inclusion complex in bioadhesive gel (HPMC) might
be further developed for safe, convenient and effective
treatment of vaginal candidasis.
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